CN101146771A - Preparation method of 2-azabicyclo-[3.3.0]octane-3-carboxylic acid derivative - Google Patents

Abstract

The present invention is aimed at a process for the preparation of compounds of the general formula (I) through the hydrogeneration of cyclization of the intermediates of the formula (II).

Description

Preparation method of 2-azabicyclo-[3.3.0]octane-3-carboxylic acid derivative

technical field

The present invention relates to a process for the preparation of compounds of general formula (I).

Background technique

Such compounds are a class of very valuable intermediates for the preparation of biologically active agents. For example, 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid can be used to prepare ACE inhibitor Ramipril_(N-(1-(S)-ethoxycarbonyl-3-phenyl-propyl) -(S)-alanyl-(S)-cis, endo-2-azabicyclo-[3.3.0]-octane-3-S-carboxylic acid) (A.Kleemann, J.Engel, Pharmaceutical Substances, 4th Edition, page 1785, Thieme Verlag Stuttgart, 2001).

A number of methods for the preparation of racemic 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid have been disclosed, for example:

Anodic oxidation of N-acylcyclopentylpyrroles followed by cyanation and hydrolysis (DE3151690).

Starting with bicyclo-[3.3.0]-nonan-2-one via Beckmann rearrangement, halogenation and Favorski rearrangement (DE 3151690).

Taking cyclopentene as the starting reactant via organic mercury compounds (DE 3300316, R. Henning, H. Urbach, Tetrahdron Letters, 24, 5343-6 (1983)).

With bromocyclopentene and serine as starting reactants, use Bu ₃ SnH intramolecular cyclization intermediate iodoalanine (DE 297620, H.Urbach, R.Henning, Heteterocycles 28, 957-65(1989)) .

By hydrogenation of tetrahydrocyclopentylpyrrole-2-carboxylic acid (WO86/00896, US 4,587,258).

Addition of formimines via 1,3-dipolar cycloaddition (L.M. Harwood, L.C. Kitchen, Tetrahedron Lett., 34, 6603 (1993)).

Possible preferred method ((A.Kleemann, J.Engel, Pharmaceutical Substances, 4th edition, page 1785, Thieme Verlag Stuttgart, 2001); EP 79022; V.Teetz, R.Geiger, H.Gaul, Tetrahedron Letters, 25, 4479-82 (1984)) comprises: at first taking serine as initial reactant, prepares 2-acetamido-3-chloropropionic acid methyl ester (DE 19941062) through 3 steps of reaction. The resulting compound is reacted with pyrrolidinylcyclopentene to give methyl cyclopentanonylacetamidopropionate. Under the action of a strong acid, accompanied by the cleavage of the amide group and the ester group, the compound obtained in the previous step is cyclized to obtain a bicyclic imidate. Subsequent catalytic hydrogenation affords racemic 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid. The reaction process is shown in Scheme 1:

plan 1:

This method mainly forms 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid in the cis-endo conformation, ie, a mixture of mainly RRR- and SSS-compounds is obtained. For resolution of the racemates, the carboxylic acid is converted into an ester, preferably a benzyl ester, which is then resolved into the diastereomerically pure bicycle by salt formation with a chiral acid. 0,0-diacyl tartaric acid (DE 3345355), optically active N-acyl-amino acids (EP115345) and mandelic acid (J.Martens, S.Lübben, Journal f.prakt.Chemie, 332, 1111-1117 (1990 )) can be used as chiral acid.

To be able to selectively remove the ester group in the final active Ramipril, benzyl esters are used for the coupling and this is therefore also preferred for the resolution of the racemate.

In a preferred method (Kleemann Engel, V.Teetz, R.Geiger, H.Gaul, Tetrahdron Letters, 25, 4479-82 (1984)), N-benzyloxycarbonyl-L-phenylalanine (Z-L- Phe-OH) for the resolution of the benzyl ester racemate. Coupling of the SSS-benzyl ester with N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-(S)-alanine (NEPA), followed by removal of the benzyl ester by hydrogenation, finally yields Ramipril (Scenario 2).

Scenario 2:

Contents of the invention

The object of the present invention is to provide a usable improved process for the preparation of intermediates of general formula (I). In particular, it is important that the method can be easily realized on an industrial scale and is superior to the methods of the prior art from an economic as well as ecological point of view.

This object is achieved according to the claims. Claims 1 to 4 are directed to a preferred process for the preparation of compounds of general formula (I). Claim 4 protects novel intermediate compounds of general formula (II). Claims 5 to 7 contain a process according to the invention for the preparation of compounds of general formula (II).

In the method for preparing a compound of general formula (I) or a salt thereof,

in,

R ¹ is H, (C ₁ -C ₈ )-alkyl, (C ₆ -C ₁₈ )-aryl, (C ₇ -C ₁₉ )-aralkyl, (C ₁ -C ₈ )-alkyl- (C ₆ -C ₁₈ )-aryl, (C ₃ -C ₈ )-cycloalkyl, (C ₁ -C ₈ )-alkyl-(C ₃ -C ₈ )-cycloalkyl, (C ₃ - C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl,

Due to the hydrogenation of a compound of general formula (II) in the presence of a catalyst,

in,

^R1 is as defined above, and

R ² is a hydrogenolyzable group,

It is very convenient to obtain the target and obtain satisfactory results. Since the ^R group in the compound of general formula (II) is a hydrogenolyzable group, a person skilled in the art can obtain the compound of general formula (I) in one step in a surprisingly simple manner, which can be immediately subjected to subsequent conventional elimination Rotational resolution without further metathesis steps or esterification. Therefore, in the background of the prior art, it is unforeseeable to realize three chemical steps (leaving of N-protecting group, cyclization and hydrogenation) in such a simple reaction step.

Within the range of variation of the aforementioned radicals, a person skilled in the art can freely select particularly advantageous radicals depending on the cost/benefit ratio. When the R ¹ group preferably uses H or (C ₁ -C ₈ )-alkyl, R ² can optionally be ring-substituted benzyl. Preferred ^R1 groups are eg methyl or ethyl. R ² may preferably be benzyl.

For the process according to the invention, the person skilled in the art can use various suitable organic solvents. Advantageous organic solvents are those which sufficiently dissolve the product used and which are inert to the reaction. Therefore, preferred organic solvents are selected from alcohols such as methanol, ethanol, isopropanol, ethers such as diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, THF, aromatic hydrocarbons such as toluene, xylene , Carboxylate such as ethyl acetate, isopropyl acetate, n-butyl acetate, secondary amides such as DMF, NMP. Very particular preference is given to using alcohols which correspond to the radical R ¹ . It is therefore extremely preferred to use ethanol or methanol as solvent.

Targeted methods can be implemented in a similar fashion to expertise. As catalysts, preference is given to using those catalysts which are capable of causing the hydrogenation of C═C and C═N double bonds and the hydrocracking of the aforementioned groups, respectively. Suitable catalysts are heterogeneous and homogeneous catalysts, especially catalysts selected from palladium, platinum, rhodium, nickel, cobalt or in Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume 4/1c, pages 14- 480, Catalysts for this purpose mentioned in Thieme Verlag Stuttgart, 1974.

Advantageously, the hydrogenation is carried out at a temperature of 0-100°C, preferably 10-80°C, particularly preferably 20-30°C.

The hydrogen pressure can be adjusted during the reaction according to a value deemed appropriate by those skilled in the art. The pressure is preferably 1-50 bar, preferably 1-30 bar, more preferably 1-20 bar.

The hydrogenation of the invention can be carried out conventionally using elemental hydrogen. In principle, however, it is also possible to carry out in the form of transfer hydrogenation in a manner known to the person skilled in the art (Houben-Weyl, Methoden der Organischen Chemie, Volume 4/1c, pages 67-76, Thieme Verlag Stuttgart, 1974).

The subject of the invention is likewise the compounds of the general formula (II) or, if R ¹ =H, the salts of the compounds of the general formula (II)

in

R ¹ is H, (C ₁ -C ₈ )-alkyl, (C ₆ -C ₁₈ )-aryl, (C ₇ -C ₁₉ )-aralkyl, (C ₁ -C ₈ )-alkyl- (C ₆ -C ₁₈ )-aryl, (C ₃ -C ₈ )-cycloalkyl, (C ₁ -C ₈ )-alkyl-(C ₃ -C ₈ )-cycloalkyl, (C ₃ - C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl, and

R ² is a hydrogenolyzable group. These compounds described herein are excellent intermediates for the preparation of compounds of general formula (I). The preferences stated above for the ^R1 and ^R2 groups apply analogously here.

In a last particular embodiment, the invention relates to the preparation of compounds of general formula (II). These compounds can be advantageously prepared by the method of the present invention, including making the compound of general formula (III)

in

R ^{and R} are as defined above,

Reaction with enamines of general formula (IV)

in

R ³ and R ⁴ may independently be (C ₁ -C ₈ )-alkyl, (C ₆ -C ₁₈ )-aryl, (C ₇ -C ₁₉ )-aralkyl, (C ₁ -C ₈ )-alkyl-(C ₆ -C ₁₈ )-aryl, (C ₃ -C ₈ )-cycloalkyl, (C ₁ -C ₈ )-alkyl-(C ₃ -C ₈ )-cycloalkyl , (C ₃ -C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl or R ³ and R ⁴ together form a (C ₂ -C ₅ )alkylene bridge optionally comprising heteroatoms. The preferences for the ^R1 and ^R2 groups mentioned immediately above apply here as well. The preferred scheme of ^R3 and ^R4 groups is that the ^R3 and ^R4 groups form a 5- or 6-membered heterocyclic ring together with a nitrogen atom. Particular preference is given to compounds of the general formula (IV) in which the ^R3 and ^R4 groups together with the nitrogen atom form a pyrrolidine, piperidine or morpholine group.

Advantageously, the process of the invention mentioned here is carried out in an organic solvent. Preferred suitable solvents are: ethers such as diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, THF, aromatic hydrocarbons such as toluene, xylene, carboxylic acid esters such as ethyl acetate, isoacetate Propyl esters, n-butyl acetate, secondary amides such as DMF, NMP, chlorinated hydrocarbons such as chloroform, dichloromethane. Particular preference is given here to halogenated organic solvents. Extreme preference is given to using chloroform or dichloromethane.

The reaction of the compound of the general formula (IV) and the compound of the general formula (III) is preferably carried out at a temperature between 0-100°C, preferably 10-50°C, particularly preferably between 15-30°C.

According to the present invention, the preparation process of the compound of general formula (I) is as follows. Similar to N-acyl derivatives (M.Bergmann, K.Grafe, Hoppe-Seylers Zeitschrift Physiologische Chem.187,187 (1930)), the urethane of formula (III) can be obtained by the simple and easy compound of formula (V)

and the urethane of formula (VI), which is also easy to obtain.

For the R ¹ and R ² radicals, the above definitions apply likewise. Preference is given here to using ethylpyruvate and benzyl-urethane. The reaction is preferably carried out in such a way that the reaction water is preferably removed by azeotropic distillation. A particularly suitable solvent is toluene. However, the person skilled in the art is familiar with more suitable solvents for this case.

Compounds of formula (III) may be obtained in the desired purity sufficient for subsequent reactions without further purification. In order to avoid undesired polymerization of the acrylic acid derivatives of formula (III), radical scavengers, preferably hydroquinone, can be added. Compounds of general formula (III) can then be added to compounds of general formula (II) to give compounds of general formula (IV) as described for the Michael reaction. In subsequent hydrogenation, the N-protecting group is removed and the compound is cyclized to finally give (I).

In contrast to the method described in EP 79022, this reaction does not require the addition of strong acids. The removal of the N-protecting group is carried out in situ by catalytic hydrogenation in the process according to the invention. This gives an intermediate of formula (II), which is very unstable in its free state (wherein ^R2 is H) and undergoes spontaneous cyclization. It is not necessary to use strong acids as required by the prior art (EP 79022).

An additional advantage of the process of the invention is that, since the ester group is preserved, compounds of formula (I) (wherein ^R is not H) do not have to be directly treated with an optically active acid (such as, for example, N-benzyloxycarbonyl-L-phenyl-alanine acid) for the resolution of racemates. A new esterification as described in EP 79022 is not necessary. Furthermore, if the hydrogenation is carried out without addition of acid, the esters of formula (I) will be obtained as free bases and can be reacted directly with optically active acids without further purification.

The thus obtained diastereomerically pure salts of 2-azabicyclo-[3.3.0]-octane-3-carboxylic acids prepared according to the invention can be resolved into their isomer. The enantiomerically enriched 2-azabicyclo-[3.3.0]-octane-3-carboxylate thus obtained can be converted to the corresponding free acid by acidic hydrolysis. The release is preferably carried out such that (S)-cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylate is dissolved in water at acidic pH and the optical activity obtained is extracted with an organic solvent Auxiliary acid and recirculation. The ester can then be hydrolyzed by heating the acidic aqueous solution. By evaporating the reaction solution, 2-azabicyclo-[3.3.0]-octane-3-carboxylic acid can be precipitated, preferably as an inner salt, but preferably as a hydrochloride. (S)-cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid can be combined with N-(1-(S)-ethoxy Carbonyl-3-phenylpropyl)-(S)-alanine (NEPA) reacts to form Ramipril_.

Thus, the targeted approach helps to considerably simplify the synthesis of the bioactive reagent Ramipril® on an industrial scale. Such a simplification cannot be expected naturally in light of the prior art background, instead the intermediates formed during the reaction are very reactive intermediate compounds capable of participating in many side reactions, such as polymerization reactions. It is therefore surprising that, despite this risk, it is possible for the three chemical reaction steps described to be one process step.

(C ₁ -C ₈ )-Alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or Octyl groups and all their bonded isomers.

(C ₁ -C ₈ )-Alkoxy corresponds to a (C ₁ -C ₈ )-alkyl group attached to the molecule via an oxygen atom.

(C ₂ -C ₈ )-Alkoxyalkyl refers to groups in which the alkyl chain is interrupted by at least one oxygen function, which does not apply to the case where two oxygen atoms are connected to each other. The number of carbon atoms refers to the total number of carbon atoms contained in the group.

A (C ₃ -C ₅ )-alkylene bridge is a carbon chain with three to five C atoms that is considered to be attached to the molecule by two different C atoms.

The radicals described in the preceding paragraphs may be mono- or polysubstituted by halogen and/or radicals comprising N, O, P, S, Si atoms. In particular alkyl groups of the abovementioned type contain one or more of the abovementioned heteroatoms in their chain or are attached to the molecule via one of these heteroatoms.

(C ₃ -C ₈ )-Cycloalkyl is understood to be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like. These groups may be substituted by one or more halogens and/or groups containing N, O, P, S, Si atoms and/or contain N, O, P, S atoms in the ring, e.g., 1-, 2 -, 3-, 4-piperidinyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3-tetrahydrofuranyl, 2-, 3-, 4-morpholinyl.

(C ₃ -C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl is a cycloalkyl group as described above which is attached to the molecule via an alkyl group as described above.

A (C ₁ -C ₈ )-acyloxy group in the context of the present invention is an alkyl group as defined above having up to 8 C atoms, which is attached to the molecule via the COO-function.

(C ₁ -C ₈ )-acyl in the context of the present invention means an alkyl group as defined above having up to 8 C atoms, which is attached to the molecule via a CO-function.

(C ₆ -C ₁₈ )-Aryl is understood to be an aromatic radical having 6 to 18 C atoms. In particular, systems including phenyl, naphthyl, anthracenyl, phenanthrenyl, or biphenyl, or the foregoing groups fused to related molecules such as indenyl systems, which may optionally be replaced by halogen , (C ₁ -C ₈ )-Alkyl, (C ₁ -C ₈ )-Alkoxy, NH ₂ , NH(C ₁ -C ₈ )-Alkyl, N((C ₁ -C ₈ )-Alkyl radical) ₂ , OH, CF ₃ , NH(C ₁ -C ₈ )-acyl, N((C ₁ -C ₈ )-acyl) ₂ , (C ₁ -C ₈ )-acyl, (C ₁ -C ₈ )-acyloxy substitution.

A (C ₇ -C ₁₉ )-aralkyl group is a (C ₆ -C ₁₈ )-aryl group which is attached to the molecule via a (C ₁ -C ₈ )-alkyl group.

(C ₃ -C ₁₈ )heteroaryl in the context of the present invention refers to five-, six- or seven-membered aromatic ring systems containing 3 to 18 C atoms, which contain, for example, nitrogen, oxygen or sulfur in the ring. heteroatoms. Such heteroatoms are especially meant, for example, 1-, 2-, 3-furyl, 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridine Base, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, Quinolinyl, phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl groups. These groups may be substituted with the same groups as the above-mentioned aryl groups.

(C ₄ -C ₁₉ )-Heteroaralkyl is understood to be a hetero-aromatic system corresponding to (C ₇ -C ₁₉ )-aralkyl.

Suitable halogens (Hal) are fluorine, chlorine, bromine and iodine.

An N-protecting group is understood to be a protecting group generally introduced in amino acid chemistry for the purpose of protecting the nitrogen atom. Groups which may be mentioned in particular are: formyl, acetyl, Moc, Eoc, phthaloyl, Boc, Alloc, Z, Fmoc and the like.

The hydrogenolyzable group is preferably an N-protecting group selected from optionally ring substituted benzyl. Suitable ring substituents are preferably 4-substituted halogen, nitro, alkyl or alkoxy derivatives (Houben-Weyl, Methoden der Organischen Chemie, Volume 15/1, page 69, Thieme Verlag Stuttgart, 1974) .

The term enantiomeric enrichment or enantiomeric excess in the context of the present invention is understood as the proportion of one enantiomer in a mixture containing its optical enantiomer which is >50% and <100% . The ee value is calculated as follows:

([Enantiomer 1]-[Enantiomer 2])/([Enantiomer 1]+[Enantiomer 2])=ee value

Nomenclature of compounds presented herein includes all possible diastereoisomers, which may also be used to name the two optical enantiomers of each diastereomer.

References mentioned in this specification are considered to be included in the disclosed content.

Detailed ways

Example

Ethyl N-benzyloxycarbonyl-2-aminoacrylate

Add 288g of ethyl pyruvate, 250g of benzyl carbamate, 2.5g of p-toluenesulfonic acid and 1g of hydroquinone to 2.5L of toluene, and reflux in a dehydrator for 9h. Then, the reaction solution was filtered using silica gel and washed with 500 ml of toluene solution. The resulting filtrate was treated with 1 g of hydroquinone and then concentrated to maximum extent using a rotary evaporator. 376 g of ethyl N-benzyloxycarbonyl-2-aminoacrylate was obtained in the form of oil, and its purity was about 90% as determined by HPLC.

1H-NMR (DMSO-D ₆ ): 1.23(t, 3H), 4.18(q, 2H), 5.11(s, 2H), 5.61(s, 1H), 5.78(s, 1H), 7.37(m, 5H ), 8.86(s, 1H).

2-N-Benzyloxycarbonylamino-3-(2-oxocyclopentyl)-propionic acid ethyl ester

366g ethyl N-benzyloxycarbonyl-2-aminoacrylate (concentration: about 90%) and 191g cyclopentenylpyrrolidine (cyclopentenopyrrolidine) were dissolved in CH ₂ Cl ₂ , and the resulting solution was stirred at room temperature for 16 h. Then, the resulting reaction solution was treated with 350 mL of acetic acid and 1 L of water, and vigorously stirred for 15 min. After phase separation, the organic phase was extracted again with a mixture of 180 mL of acetic acid and 1 L of water, followed by washing with 500 mL of water. The solution was filtered through silica gel and the solvent was completely evaporated under vacuum. Finally, 463 g of ethyl 2-N-benzyloxycarbonylamino-3-(2-oxocyclopentyl)-propionate were obtained in the form of oil.

¹ H-NMR (DMSO-D ₆ ): 1.17 (m, 3H), 1.51 (m, 2H), 1.69 (m, 1H), 1.90 (m, 1H), 2.09 (m, 5H), 4.09 (m, 2H), 4.24 (m, 1H, major rotamer), 5.05 (s, 2H, major rotamer), 7.34 (m, 5H), 7.75 (d, IH, major rotamer).

cis-2-Azabicyclo-[3.3.0]-octane-3-carboxylic acid ethyl ester

Dissolve 200g of 2-N-benzyloxycarbonylamino-3-(2-oxocyclopentyl) ethyl propionate in 1000mL of ethanol, add 5g of catalyst (5% Pd on the active C), then under 5bar conditions hydrogenation. After 4 hours of reaction, the reaction raw materials were no longer detected by HPLC. The catalyst was filtered and the filtrate was concentrated to a maximum. This gave 103 g of ethyl cis-2-azabicyclo-[3.3.0]-octane-3-carboxylate as a pale yellow oil which was reacted further without further purification. According to the 1H-NMR spectrum, the cis-endo isomer accounts for 78 mol%.

¹ H-NMR (DMSO-D ₆ main isomer):

1.18(t, 3H), 1.30(m, 1H), 1.51(m, 6H), 2.19(m, 1H), 2.48(m, 1H), 3.50(dd, 1H), 3.53(m, 1H), 4.07 (dq, 2H).

(s)-cis-endo-2-Azabicyclo-[3.3.0]-octane-3-carboxylic acid ethyl ester Z-L-phenylalanine salt

Add cis-2-azabicyclo-[3.3.0]-octane- 3-Carboxylic acid ethyl ester. Add 1L MTBE to the supernatant. After adding seed crystals, it was stirred at room temperature for 4 h, and the suspension became viscous.

Filtered, the resulting product was washed twice with 100mL MTBE, and dried in vacuo at 50°C to obtain 66.4g (s)-cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid ethyl ester Z-L- Phenylalanine salt.

¹ H-NMR (DMSO-D ₆ ): 1.18(t, 3H), 1.33(m, 1H), 1.37(m, 1H), 1.54(m, 5H), 2.21(m, 1H), 2.94(ddd, 2H), 3.57 (m, 2H), 4.08 (dq, 2H), 4.15 (m, 1H), 4.97 (s, 2H), 7.27 (m, 5H), 7.46 (d, 1H).

(s)-cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylate hydrochloride

In 20 mL of water and 40 mL of MTBE was added 3.0 g of (s)-cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid ethyl ester Z-L-phenylalanine salt. After adding 1 mL of 37% hydrochloric acid to the obtained suspension, the mixture was stirred until the reaction liquid became clear. The aqueous phase was separated and re-extracted with 40 mL MTBE. The organic phase was roughly stripped under vacuum, and the resulting solution was treated with 14 mL of 37% hydrochloric acid, and then heated at 100-105 °C for 14 h. The resulting mixture was evaporated in vacuo, the residue was worked up with 10 mL of acetic acid and evaporated again. The resulting residue was dissolved in 10 mL of acetic acid, and then MTBE was added for crystallization. This gave 0.95 g of (s)-cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid hydrochloride.

¹ H-NMR (DMSO-D ₆ ): 1.45 (m, 1H), 1.60 (m, 3H), 1.74 (m, 2H), 1.99 (m, 1H), 2.45 (m, 1H), 2.80 (m, 1H), 3.98 (m, 1H), 4.21 (dd, 1H), 8.70 (s, broad, 1H), 10.60 (s, broad, 1H), 13.80 (s, broad, 1H).

Claims (7)

1. A method for preparing a compound of general formula (I) or a salt thereof,

in, R ¹ is H, (C ₁ -C ₈ )-alkyl, (C ₆ -C ₁₈ )-aryl, (C ₇ -C ₁₉ )-aralkyl, (C ₁ -C ₈ )-alkyl- (C ₆ -C ₁₈ )-aryl, (C ₃ -C ₈ )-cycloalkyl, (C ₁ -C ₈ )-alkyl-(C ₃ -C ₈ )-cycloalkyl, (C ₃ - C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl, characterized in that the compound of general formula (II) is hydrogenated in the presence of a catalyst,

in, ^R1 is as defined above, and R ² is a hydrogenolyzable group. 2. The method according to claim 1, characterized in that R ¹ is H or (C ₁ -C ₈ )-alkyl, R ² is optionally ring substituted benzyl. 3. Process according to claim 1 and/or 2, characterized in that the hydrogenation is carried out in an alcohol as solvent. 4. Compounds of the general formula (II) or, if R ¹ =H, salts of compounds of the general formula (II)

in, R ¹ is H, (C ₁ -C ₈ )-alkyl, (C ₆ -C ₁₈ )-aryl, (C ₇ -C ₁₉ )-aralkyl, (C ₁ -C ₈ )-alkyl- (C ₆ -C ₁₈ )-aryl, (C ₃ -C ₈ )-cycloalkyl, (C ₁ -C ₈ )-alkyl-(C ₃ -C ₈ )-cycloalkyl, (C ₃ - C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl and R ² is a hydrogenolyzable group. 5. the preparation method of the described compound of claim 4 is characterized in that Make the compound of general formula (III)

in R ^{and R} are as defined in claim 4, Reaction with enamines of general formula (IV)

in R ³ and R ⁴ are independently (C ₁ -C ₈ )-alkyl, (C ₆ -C ₁₈ )-aryl, (C ₇ -C ₁₉ )-aralkyl, (C ₁ -C ₈ ) -alkyl-(C ₆ -C ₁₈ )-aryl, (C ₃ -C ₈ )-cycloalkyl, (C ₁ -C ₈ )-alkyl-(C ₃ -C ₈ )-cycloalkyl, (C ₃ -C ₈ )-cycloalkyl-(C ₁ -C ₈ )-alkyl or R ³ and R ⁴ together form a (C ₂ -C ₅ )alkylene bridge. 6. Process according to claim 5, characterized in that the reaction is carried out in a halogenated organic solvent. 7. Process according to claim 5 and/or 6, characterized in that the reaction is carried out at 20-100°C.